The major goals of this program project can be divided into three main areas of investigation: a) an examination of the factors important in the development of irreversible ischemic damage both during the ischemic insult itself and during the reperfusion phase, b) an examination of potential interventions which may favorably influence the outcome following an ischemic event, and c) studies of normal cerebral function, regulation of cerebral blood flow and metabolism, and the abnormalities that occur in these processes in ischemic conditions affecting the brain. The projects in this application are closely inter-related by their focus on an attempt to better understand the normal control of cerebral function, the alterations that occur in those functions produced by ischemic insults to the brain, the factors responsible for the cerebral damage produced and the development of means to prevent that damage. The techniques we have at our disposal allow us to look at these interrelated problems from the subcellular level, to animal models of stroke, to clinical studies in man. The close interaction of basic scientists and clinical researchers in this program project allows information obtained from studies at the subcellular and animal model levels to be applied to the clinical situation and conversely problems of clinical importance can be explored rapidly with the tools available to the basic scientists.